[unreadable] The peroxisome proliferator activated-receptor ( (PPAR() plays a central role in energy homeostasis by initiating transcription of multiple genes in fatty acid and glucose metabolism, while concomitantly downregulating genes in insulin signaling. In liver, PPAR( induces transcription of many genes involved in fatty acid degradation by (-oxidation, fatty acid uptake and transport, and lipoprotein metabolism. Thus, PPAR( is responsible for control of a number of lipid metabolic proteins that may contribute to obesity, diabetes, lipotoxicity, and subsequent cardiovascular disorders. However, relatively little is known regarding either the mechanisms that regulate the availability of endogenous fatty acyl-CoA ligands to the nucleus for interaction with PPAR( or the effect of these ligands on PPAR( interaction with heterodimer partners. Although it is known that PPAR( must heterodimerize with either the retinoid X receptor (RXR) or the liver X receptor (LXR) prior to binding DNA response elements, for transcriptional regulation, surprisingly little is known about the effect of endogenous ligands on the choice of heterodimer partners. Furthermore, the effect of PPAR( ligands on heterodimer partners is incompletely resolved. In order to address these issues, this proposal is focused in two phases: First, the 'mentored phase' will: 1. Resolve whether PPAR(-mediated transcription of genes is regulated by long-chain fatty acyl-CoAs (LCFA-CoA). 2. Determine the effect of LCFA-CoA on the molecular interaction of PPAR( with L-FABP. Second, the 'independent phase' will: 3. Determine if LXR( binds LCFA-CoA with high affinity, in the physiological range of nuclear LCFA-CoA levels. 4. Elucidate the effect of LCFA-CoA on the molecular interaction of PPAR( with LXR(. It is hoped that the results of this work will provide a mechanistic role of LCFA-CoAs in nuclear receptor regulation. [unreadable] Relevance to Public Health: This work aims at studying a protein whose abnormal expression/regulation is associated with obesity, diabetes, and cardiovascular disease. This research is a step towards the development of new methods and more efficient drugs for the treatment of such disorders. [unreadable] [unreadable]